Bis-(phosphorylated anthralin)compounds and process for preparing same

ABSTRACT

PHOSPHORYLATED BIS-ANTHRACENETRIOL COMPOUNDS OF THE STRUCTURE:   2-W,8-Z,12-Y,18-X,5,15-DI(O=),5,6A-(-O-),15,16A-(-O-)   DIANTHRA(4,4A,10-CD:4&#39;&#39;,4A&#39;&#39;,10&#39;&#39;-IJ)-1,3,7,9-TETRAOXA-     2,8-DIPHOSPHACYCLODODECANE WHEREIN W, X, Y AND Z ARE SELECTED FROM THE GROUP CONSISTING OF HYDROGEN, LOWER ALKYL, HALO-ALKYL, ACETOXI-ALKYL, CARBOXYL CARBOALKYLOXI, ALKYLOXIALKYL, HALOGEN AND NITRO WHEREIN SAID ALKYL IS FROM 1 TO 3 CARBON ATOMS IN CHAIN LENGTH, ARE PREPARED BY PHOSPHORYLATING APPROPRIATE 1,8,9 TRIHYDROXI-ANTHRACENE OR 3-SUBSTITUTED-1,8,9 - THRIHYDROXIANTHRACENE COMPOUNDS IN THE PRESENCE OF AN AROMATIC OR ALIPHATIC TERTIARY AMINE BASE, PREFERABLY PYRIDINE. THE RESULTANT COMPOUNDS ARE USEFUL IN THE TREATMENT OF PSORIASIS, SEBORRHEA, ECZEMA, INFLAMMATION AND ARTHRISTIS. PHARMACEUTICAL COMPOSTIONS SUCH AS OINTMENTS, LOTIONS, SHAMPOOS AND DETERGENT CAKES, BESIDE ORAL AND RECTAL APPLICATION FORMS, CONTAINING THE AFORESAID COMPOUNDS ARE DESCRIBED TOGETHER WITH METHODS OF THEIR PREPARATION AND THEIR USE IN THERAPY.

'United States Patent 3,792,129 BIS-(PHOSPHORYLATED ANTHRALIN) COM-gOUNDS AND PROCESS FOR PREPARING AME Charles Aubrey Friedmann, Florence,Italy, Peter Hofer,

Liestal, Switzerland, and Winthrop E. Lange, Greenwich, Conn., assignorsto Mundipharma AG., Rheinfelden, Switzerland No Drawing. Filed Sept. 8,1971, Ser. No. 178,829 Int. Cl. C07d 103/04; A01n 9/36 US. Cl. 260-927 R14 Claims ABSTRACT OF THE DISCLOSURE Phosphorylated bis-anthracenetriolcompounds of the structure:

l O=P P=O o 0 I I wherein W, X, Y and Z are selected from the groupconsisting of hydrogen, lower alkyl, halo-alkyl, acetoxi-alkyl,carboxyl, carboalkyloxi, alkyloxialkyl, halogen and nitro wherein saidalkyl is from 1 to 3 carbon atoms in chain length, are prepared byphosphorylating appropriate l,'8,9- trihydroxi-anthracene or3-substituted-l,8,9 trihydroxianthracene compounds in the presence of anaromatic or aliphatic tertiary amine base, preferably pyridine. Theresultant compounds are useful in the treatment of psoriasis, seborrhea,eczema, inflammation and arthritis. Pharmaceutical compositions such asointments, lotions, shampoos and detergent cakes, beside oral and rectalapplication forms, containing the aforesaid compounds are describedtogether with methods for their preparation and their use in therapy.

The present invention relates to certain phosphorylated bis-anthracenetriol compounds and pharmaceutical compositions containing the same, themethods for their preparation and the methods for their use in treatingdermatologic disease, inflammation and arthritis. In particular itrelates to compounds having the formula:

3,792,129 Patented Feb. 12, 1974 containing the same; the methods forthe preparation of said'compounds and said pharmaceutical compositions,and the method for treating seborrhea, psoriasis and eczema,inflammation and arthritis.

Psoriasis is a chronic, and occasionally an acute, relapsing,papulosquamous skin disease of unknown etiology, that is generally notresponsive to the presently available therapeutic agents. While earlylesions are more amenable to treatment than long-standing ones, so thatthe acute attack will usually abate within a reasonably short period oftime, recurrence is almost always certain. It is well recognized thatprolonged use of the conventional therapeutic agents utilized to treatpsoriasis will reduce the elfectiveness of the agent resulting in anexcerbation of the disease in a more serious and resistant form.

The connection between psoriasis and reticuloendothelial disorders hasrecently been shown in the literature wherein simple anthrolonecompounds have been found to cause a temporary remission of thepsoriatic lesion and at the same time to alleviate symptoms ofarthritis. That anthracene compounds exert a beneficial dermatologicaction has been known for many years and 1,8-dihydroxy- 9-anthrone hasbeen used in the therapy of skin disease for a long time. However allanthrone compounds hitherto utilized in topical therapy possess thecommon inherent limitation in that these are rapidly oxidized to thequinone form which destroys their therapeutic potential. Furthermore,the oxidized anthrone compound acts as a toxic tissue irritant and doesnot penetrate the skin barrier to affect the cellular physiology whereinthe abnormality resides. To further complicate the therapeutic use ofthe presently available anthracenic compounds is the knowledge thatultra-violet light increases their oxidative potential and yet,ultra-violet light remains an important part of the therapeutic regimenin the treatment of psoriasis.

In the development of the understanding of psoriasis by the use of theelectron microscopic cytoplasmic differentiation techniques, the role ofenzymes in the overall oxidation potential of the psoriatic cell wasdemonstrated. Primary tissue cultures obtained from untreated andtreated psoriatic patients demonstrated that there was a differentiationin the ultra-structure of the cells of the psoriatic lesion which isaltered in the direction of the normal tissue cell when these weretreated with an enzyme inhibitor substance and/ or anti-inflammatoryagents. Thus it was shown that cellular enzymes involved in glycolysiswere increased in the psoriatic lesion while the enzymes involved in fatmetabolism decreased. Furthermore, with the electron microscope it wasdemonstrated that acid-phosphorylase activity shifted from theintracellular level in the normal epidermis, to the extra-cellular levelin the ortho and para-keratotic epidermal tissue.

Seborrheic dermatitis is a chronic erythematous, scaling inflammation ofthe skin often occurring in conjunction with psoriasis and eczema. Thepredominant symptom is a dysfunction of the sebaceous gland oftenaccompanied by a predisposition to acute and chronic skin infections.Eczema has become synonymous with chronic dermatitis and ischaracterized by an acute or chronic superficial scaling. While theexact etiology for both seborrhea and eczema is unknown, it has beensuggested to be a cellular enzyme disturbance resulting in an abnormaltissue metabolism. Eiforts to establish a relationship between cellularnutrients and the diseased state have been generally failed andtreatment has been virtually entirely limited to symptomatic approaches.Thus, keratolytic agents, scaling agents, counter-irritants, dryingagents and a host of other symptom-specific dermato-pharmacologic agentshave been employed over the years, with varying degrees of success.While patterns have been developed in treating certain of thesediseases, as for example, the use of sulphur and keratolytic agents inthe treatment of seborrhea, a common therapeutic approach to thesediseases, remains to be developed. It is suggested that psoriasis,seborrhea, eczema and the related dermatitis possess the commondenominator of abnormal cellular respiratory oxidative enzyme activityand that enzyme inhibitory agents hold promise in ultimately resolvingthese pathologic problems.

It was unexpectedly found that certain bis-(phosphorylated anthracenetriol) compounds were capable of beneficially affecting the psoriaticlesion, seborrheal conditions and eczema, inflammation and arthritis.Moreover, the aforesaid bis-(phosphorylated anthracene triol)derivatives were capable of penetrating through the keratin tissuebarrier and were not affected by oxidation and exposure to light.

The class of bis-(phosphorylated anthracene triol) derivativesrepresents a hitherto unknown class of chemical compounds in thatphosphorylation results in the formation of a bis-molecular structurethat is sterically hindered to reduce the potential for degradativechemical changes and yet, capable of affecting chemical reactions on thecellular level. Furthermore, similar pharmacologic activity is obtainedby appropriate substitution in the three and/or six positions. By theintroduction of a carboxyl group into the molecule Water soluble andinsoluble metal salts may be formed.

The new bis-(phosphorylated anthracene triol) compounds have thefollowing generic structural formula:

and (1,1,8,8',9,9')-dianthracenetriyl (1,9,8'), (1',9,8)- diphosphatemay be considered to be the parent compound for the new class. Throughthe use of appropriate starting materials, substituted in the three orsix position, the corresponding (3,3'), (6,6) or (3,3,6,6) substitutedphosphorylated dianthracene triol compounds are obtained. Preferredcompounds of this series are:

wherein W, X, Y and Z represents a group selected from the groupsconsisting of hydrogen, lower alkyl (preferably methyl), haloalkyl(preferably chlorornethyl), acetoxialkyl (preferably acetoximethyl),carboalkyloxi, alkyloxi (preferably methoxi), carboxyl, halogenalkyloxialkyl and nitro wherein the alkyl group is from 1 to 3 carbonatoms in chain length.

Dianthracenetriyl (1,1',8,8,9,9') diphosphate is prepared through thephosphorylation of 1,8,9, trihydroxianthracene. Phosphorus oxychlorideis a preferred phosphorylating agent and the synthesis is conducted inpyridine or a suitable tertiary amine as a catalyst solvent. Thereaction is exothermic and rapidly proceeds to completion attemperatures above 50 C. 3-mono-substituted bis-(phosphorylated-anthracene triol) compounds occur as a mixture of threeisomers, (3,3'), (6,6), (3,6') substituted compounds.'Whencrysophanol-9-anthrone is reacted with phosphorus oxychloride, thedimethyl-dianthracene triyl (l,1',8,8,9,9')-diphosphate is obtained as amixture of the (3,3), (6,6), and (3,6)-dimethyl, isomers. In a similarmanner, when 1,9,8-trihydroxi anthracene 3-acetoximethyl, 1,9,8trihydroxy-anthracene-3-alkyloxi-3-alkoxialkyl-l,9,8-trihydroxy-anthracene,wherein said alkyl group is from 1 to 3 carbon atoms in chain length and3- chloromethyl-1,8,9-trihydroxyanthraceen are phosphorylated, then thecorresponding substituted bis(phosphorylated anthracenetriyl)derivativeis obtained.

Dicarboxy-dianthracenetriyl l,1,8,8,9,9')-diphosphate is obtained as amixture of (3,3'), (6,6) and (3,6) substituted compounds, and is capableof forming an alkali metal salt, soluble in water as well as waterinsoluble metallic salts through the salt-forming properties of thecarboxyl group. Di-(chloromethyl)-dianthracenetriyl(1,l',8,8',9,9')-diphosphate is obtained through the phosphorylation of3-chloromethyl-1,8,9, trihydroxyanthracene.

The bis-(carbethoxi-anthracenetriyl)-(1,1,8,8,9,9')-diphosphate isobtained through the phosphorylation of 3- carbethoxi- 1,8,9trihydroxy-anthrene and bis-(acetoximethyl-anthracenetriyl)-(1,l',8,8',9,9')-diphosphate is obtainedthrough the phosphorylation of 3-acetoximethyl 1,8-dihydroxy-9-anthrone.

The corresponding bis-(alkyloxialkyl-anthracenetriyl (1,l,8,8',9,9)-diphosphate, wherein said alkyl group is from 1 to 3 carbonatoms in chain length, is prepared by the phosphorylation of theappropriate:

3-methoxi-methyll ,8,9-trihydroxy-anthracene,3-ethoxialkyl-1,8,9-trihydroxy-anthracene,3-ethoxi-methyl-l,9,8-trihydroxy-anthracene,3-propoxipropyll,9,8-trihydroxy-anthracene,3-isopropoximethyl-1,9,8-trihydroxy-anthracene,3-propoximethyl-1,9,8-trihydroxy-anthracene,

in a solvent selected from the group of pyridine and tertiary amines.

The bis-anthracenetriol phosphorylated compounds are obtained ascrystalline substances, yellow to brown in color, melting above 300 C.,insoluble in water, and little soluble in alcohol, propylene glycol,acetone and chloroform. The compounds are stable and without odor.Elementary analysis reveals a good agreement with the theoretical valuesto establish the structure and composition of the new compounds.

The new compounds have a characteristic infrared spectrum. Some isomericforms of the substituted dianthracene triol phosphorylated compounds maybe separated by thin layer chromatography.

The phosphorylation reaction is preferably conducted with phosphorusoxychloride or trichloride for the synthesis of the correspondingphosphites and a hydrogen chloride entrapment catalyst solvent, as forexample, pyridine, or a suitable liquid tertiary amine. The ratio ofphosphorus oxychloride to the appropriate anthrone is 1 molar equivalentof phosphorus oxychloride for each mol of anthralin compound although aslight excess of from 2 to 5% of phosphorus oxychloride is preferred.Under certain conditions it may be found desirable to increase the ratioof phosporus oxychloride to anthralin compound four-fold. The reactionis exothermic and proceeds to completion without the aid of heat.Although the compounds are heat stable, the preferred temperature rangefor the reaction is between 50 C. and C., maintained for a period offrom one to four hours.

At the conclusion of the synthetic reaction, the mixture is allowed tocool to room temperature, whereupon the solid separated material isfiltered, washed with pyridine and cold water and dried. An alternateprocedure is to pour the mixture onto cracked ice and then filtering theinsoluble material which is washed with pyridine to remove any unreactedreagent and dried. Recrystallization may be accomplished by dissolvingthe compound in acetone, adding water to the point of clouding and thensetting aside to crystallize in the cold. Still another alternatecrystallizing procedure is to dissolve the dried new compound in boilingalcohol and crystallizing in the cold.

When used therapeutically, the powdered active compound described abovemay be applied directly to the lesion or skin area after being treated.Such use provides the maximum tissue stimulant effect and is onlyindicated in certain acute states. In the usual course of therapy, theactive compound is incorporated into a pharmaceutically acceptablevehicle to form an ointment, lotion, shampoo, or cleansing cakecomposition which is applied to the affected area from one to six timesdaily or tablets for oral application.

Ointments are prepared by combining the selected active ingredient witha pharmaceutically acceptable ointment base so that the range inconcentration of the selected new compound is between 0.1 percent to 15percent by weight. The ointment base may be either a hydrophilic orlipophilic emulsion base or a prepared ointment preparation such as coldcream, hydrophylic petrolatum U.S.P., or hydrophylic ointment base,U.S.P. or an oleaginous or Water-soluble carrier such as petrolatum orpolyethylene glycol. The method of incorporating the active ingredientin the selected active ointment base may be by levigation in the cold ordispersion in the hot molten base.

A lotion containing the new phosphorylated anthralin compounds may beprepared by dispersing the selected active ingredient in an aqueous orhydroalcoholic vehicle. Suitable suspending agents and/ or a thickeningagent may be added as well as perfume and coloring substances. Suchsuspending agents as hydrated methyl cellulose and carboxy methylcellulose may be used advantageously. Surface-active agents such assodium lauryl sulfate will facilitate the dispersion of the activeingredient throughout the lotion vehicle, as well as to confer abeneficial penetrating capacity to the lotion.

The lotion vehicle may be either water, alcohol or mixtures of the same.Medicated or aromatic pharmaceutical waters may also be used in thepreparation of a lotion and glycerin and propylene glycol may be addedto provide special dermatologic properties, if desired. It will be foundbeneficial to utilize an alcoholic or an hydroalcoholic tion in certaininstances in which case, the concentration of alcohol may be as high as70 percent and as low as 10 percent. The concentration of the selectedactive ingredient in the lotion will range from 0.1 to percent, byweight.

It will be found useful to prepare cleansing compositions containing thenew compounds and such preparations may be in either liquid or soliddosage forms. Liq uid cleansing preparations are preferably used totreat the hair, scalp and other body areas wherein selective control ofthe medication is desired. Such liquid preparations containing theactive phosphorylated compounds may be prepared as shampoos or liquidsoaps and contain from 0.1 to 25 percent by weight of the selected newphosphorylated anthracene triol derivatives described herein. Theaforesaid liquid cleansing preparations may be prepared in an aqueousvehicle containing from 5 to 40 percent by weight of a non-ionic oranionic surface-active compound, and from 0.1 to 25 percent by weight ofthe selected active compound. Up to 25 percent of glycerin, propyleneglycol or a polyethylene glycol having a molecular weight of from 200 to800 may be added if desired. Suitable perfumes and coloring agents mayalso be added.

The solvent for the preparation of the liquid cleansing preparations isusually water, although small amounts of alcohol may also be added.Oil-base liquid preparations may also be used, in which case the solventmay be a bland vegetable oil, as for example, cotton-seed oil,poppy-seed oil, olive oil, peanut oil, sesame-seed oil or mixtures ofthese. From 5 to 10 percent of a fatty alcohol may also be added, ifdesired. The cleansing compound may be a non-ionic or anionicsurface-active preparation and is used in concentrations of from 5 to 35percent by weight.

It may be found useful to prepare a liquid cleansing concentrate, inwhich case the active phosphorylated compound is mixed directly With thedetergent carrier. The concentration of detergent in such preparationsmay be as high as 85 percent by weight and the solvent for suchpreparations may be either Water or oil. It is especially important thatthe pH of such liquid cleansing solutions be no greater than pH 6.

When a solid cleansing bar is preferred, then from 0.1 percent to 25percent by weight of the selected new phosphorylated compound is mixedwith a pharmaceutically acceptable diluent as for example, apolyethylene glycol compound having a molecular weight of from 1,000 to6,000, a higher fatty alcohol or fatty acid and mixtures of the same,and to this is added from 5 to 35 percent by weight of apharmaceutically compatible surface-active compound as for example, anon-ionic, or anionic detergent compound. Of critical importance is theavoidance of detergents that are alkaline in reaction or are active inthe alkaline range, since a pH above pH 6 will tend to decompose the newcompound to form a red color. It is for this reason that the alkalinesoaps are to be avoided. In preparing the bar either an extrusion,stamping or hotpour method of manufacture may be used.

The liquid cleansing preparation and the solid detergent bar containingthe active ingredient are used for cleansing as well as treating theaffected area. The method for the use of these preparations is to wetthe affected area and apply the shampoo or solid detergent bar to thesite and to develop a copious lather. The lather is permitted to remainin situ for at least five minutes and then rinsed. The process may berepeated if desired. While the detergent bar may be used as often asdesired, the shampooing of a hairy area will vary from once a week tofour times weekly depending upon the specific patients need.

EXAMPLE 1 To a 3 neck flask, fitted with a stirrer and inlet tube and anitrogen gas inlet and outlet flow tube is placed a suspension of gms.of 1,8-dihydroxy-9-anthrone in 200 ml. of pyridine. The supernatantoxygen is removed by flushing with nitrogen and a steady stream ofgaseous nitrogen is continued to maintain an oxygen-free atmosphere. Themixture is stirred and a solution of 33.1 ml. of phosphorus oxychloride(POCl dissolved in 200 m1. of pyridine is added in small increments.When all of the phosphorus oxychloride has been added the mixture iswarmed to about 80 C. for approximately 2 hours and then cooled to roomtemperature. The mixture is filtered and the separated crystallinematerial washed with cold pyridine and water until there is no furtherchloride ion present in the wash-water. The crystals on the filter aredried and are dianthracenetriyl l,1,8,8',9,9')-diphosphate.

The new compound, dianthracenetriyl (l,l,8,8,9,9')- diphosphate has amolecular weight of 540 determined by mass spectrometry and an empericalformula of It analyzes in good agreement with the theoretical values forcarbon and hydrogen (percent carbon, calculated 62.23%, found 61.93;percent hydrogen, calculated, 2.61, found, 2.99%). The followingstructural formula 7 may be postulated for dianthracenetriyl(1,1,8,8',9,9)-

diphosphate:

OFF} P The new compound is a yellow crystal, without odor, melting above300 C. It is insoluble in water, slightly soluble in ethanol andpropylene glycol, acetone and chloroform. When treated with dilutealkali, it goes into solution, with decomposition, forming a red color.

EXAMPLE 2 In a suitable flask containing 50 ml. of pyridine is added12.5 gm. of chrysophanol-9-anthrone and a solution of 4.9 ml. ofphosphorus oxychloride (POCl dissolved in ml. of pyridine is added, insmall increments, with stirring. The supernatant air is replaced withgaseous nitrogen and the mixture is warmed to 80 C. for a period ofabout 2 hours, while stirring, after which time it is allowed to cool toroom temperature. Yellow to brown crystals separate and are filtered,washed with pyridine and water and air-dried.

The formed compounds are the isomericbis-(methylanthracenetriyl)-(1,1',8,8,9,9)-diphosphates, having anemperical formula of C H O P- and a molecular weight of 568. Thecompound has the following analysis: carbon calculated: 63.39; found,63.4; 63%; hydrogen calculated: 3.19; found 3.96, 3.46.

The new compound melts above 300 C. and is insoluble in water, solublein ethanol and propylene glycol and extremely soluble in acetone andchloroform. It is slowly decomposed by dilute alkali, gradually turningred in color.

Bis-(methylanthracenetriyl) 1,l,8,8,9,9)-diphosphate is a mixture of the(3,3), (6,6), and (3,6) dimethyl isomers, which may be partiallyseparated by repeated chromatography. The new compounds have thefollowing postulated structural formula:

The 3,3 compound, wherein X and Z are methyl groups and W and X arehydrogen atoms. The 6,6 compound, wherein W and Y are methyl groups andX and Z are hydrogen atoms. The 3,6 compound, wherein X and Y are methylgroups and W and Z are hydrogen atoms.

EXAMPLE 3 In a suitable container fitted with a stirrer and a gas inlettube is placed a solution of 28.5 gm. of1,8-dihydroxy-9-anthrone-3-carboxylic acid dissolved in 100 ml. ofpyridine. Gaseous nitrogen is bubbled through the solution and 33.5 gm.of phosphorus oxychloride -(POCl dissolved in 200 ml. of pyridine isadded in small increments while stirring. The mixture is warmed to aboutC. for approximately two hours and then cooled to room temperature,treated with water, filtered and the crystalline material washedwithcold pyridine and water. The solid, crystalline infiltrate is driedand is dicarboxi-dianthracenetriyl (l,1',8,8,9,9)-diphosphate. The newcompound, is odorless and has a molecular weight of 628 with anemperical formula of C H O P The new compound exists in three isomericforms and is postulated to have the following structure:

The 3,3 compound, wherein X and Z are carboxyl groups and W and Y arehydrogen atoms.

The 6,6 compound, wherein W and Y are carboxyl groups and X and Z arehydrogen atoms.

The 3,6 compound, wherein X and Y are carboxyl groups and W and Z arehydrogen atoms.

The new compound is yellow to brown in color, with a melting point above300 C. The formed new compound is insoluble in water, slightly solublein ethanol and propylene glycol, acetone and chloroform.

The new compound forms a metallic salt when treated with solutions orsuspensions of metallic Oxides, metallic hydroxides, metalliccarbonates, and metallic bicarbonates, and also forms the respectivesalt when reacted with divalent and trivalent metallic halogen, sulfate,nitrate compounds.

EXAMPLE 4 In a suitable container fitted with a stirrer and a gas inlettube is placed 29 gm. of 3-acetoximethyl-1,8-dihydroxy-9-anthrone andml. of pyridine. Gaseous nitrogen is bubbled through the mixture and15.2 gm. of phosphorus oxychloride (POCl dissolved in 100 ml. pyridine,is added in small increments with stirring. When all of the phosphorusoxychloride has been added, the mixture is warmed to 80 C. for a periodof at least one hour, after which time it is cooled to room temperature.The mixture is set aside to crystallize and the crystals are filtered,washed with pyridine and water and dried. The dried compound is the bis-8-acetoximethyl-anthracenetriyl)(1,1',8,8',9,9)-diphosphate. Thecompound may be recrystallized from acetone.

The formed new compound is a yellow crystalline substance with a meltingpoint above 300 C. and a molecular weight of 684 and an empericalformula of C H O P The new compound is obtained as a mixture of threeisomeric forms and the following structural formula may be postulated:

The 3,3: wherein X and Z are a acetoximethyl group and W and Y arehydrogen atoms.

The 6,6: wherein W and Y are a acetoximethyl group and X and Z arehydrogen atoms. The 3,6: wherein X and Y are a acetoximethyl group and Wand Z are hydrogen atoms.

EXAMPLE To a solution of one-hundredth gram mol of 3-chloromethyl1,8-dihydroxy-9-anthrone dissolved in 20 ml. of pyridine is added 0.13gm. mol of phosphorus oxychloride (P001 dissolved in 5 cc. of pyridineand the whole stirred overnight. The mixture is then decomposed bypouring onto cracked ice and filtered. The solid material remaining onthe filter is washed with pyridine and dissolved in acetone. The acetonesolution is diluted with water to the point of clouding and set aside ina refrigerator to crystallize. The crystals are filtered and air-dried.The dried crystalline compound is di(methylchloro)-dianthracenetriyll,l,8,8',9,9) -diphosphate.

The new compound is yellow to brown in color with a melting point above300 C. and is insoluble in water, slightly soluble in ethanol andpropylene glycol and soluble in acetone and chloroform. The new compoundhas a molecular Weight of 37 (636, 638, 640) with an emperical formulaof C H Q O P The new compound is a mixture of three isomeric forms andthe following structural formula may be postulated.

The 3,3 compound, wherein X and Z is the chloromethyl group and W and Yare hydrogen atoms.

The 6,6 compounds, wherein W and Y is the chloromethyl group and X and Zare hydrogen atoms.

The 3,6 compound, wherein X and Y is the chloromethyl group and W and Zare hydrogen atoms.

EXAMPLE 6 In place of the 3 acetoximethyl-1,8-dihydroxy-9-anthronedescribed in Example 4, there may be substituted in equal molecularproportions, 1,8-dihydroxy-9-anthrone- 3-ethyl carboxylate. Theremainder of the steps bein the same and the corresponding compoundformed is the bis- (anthracenetriyl carboxylate)(1,1,8,8',9,9')-diphosphate. The compound is a mixture of three isomericcompounds and has the following postulated structure:

The 3,3 compound, wherein X and Z is ethyl carboxylate and W and Y arehydrogen atoms.

10 The 6,6 compound, wherein W and Y is ethyl carboxylate and X and Zare hydrogen atoms. The 3,6 compound, wherein X and Y is a ethylcarboxylate and W and Z are hydrogen atoms.

EXAMPLE 7 To a suspension of 0.01 gm. mol of 3-methoxymethyl-1,8-dihydroxy-9-anthrone in 10 ml. of pyridine is added 0.01 gm. mols ofphosphorus oxychloride dissolved in 5 ml. of pyridine. The mixture isstirred, warmed to 60 C. for a period of four hours and then cooled toroom temperature. The separated solid material is filtered, washed withpyridine and Water and dried. The formed compound is thebis-(3-methoxymethyl-anthracenetriyl)(l,l,8,8',9, 9)-diphosphate andoccurs as a mixture of three isomeric forms with the followingpostulated structural formula:

wherein the 3,3 substituted compounds, the X and Z is the methoximethylgroup and the W and Y are hydrogen atoms, and the 3,6 substitutedcompound, wherein X and Y is the methoximethyl group and the W and Z arehydrogen atoms, and the 6,6 substituted compound, wherein W and Y aremethoximethyl groups and X and Z are hydrogen atoms.

In a similar manner, utilizing the following substituted anthronecompounds as reagents the corresponding bis- (alkyloxialkylauthracenetriyl) (l,1',8,8',9,9')-diphosphate compound is obtained.

Corresponding formed bis(alkyloxialkyl arliltlracenetrlyl)(1,1,8,8,9,9)-diphosp a e Bis-(ethioxiethyl-anthracenetriyl)(1,1,8,9,9)-diphosphate. Bis-(ethioximethyl-anthracenetliyl)(1,1,8,8,9,9)-diph0sphate. Bis-(propoxipropyl-anthracenetriyl) (1,1',8,8,9,9)-diphosphate. Bis-(isopropoxi isopropyl-anthracenetriyl) (1,1,8,8 ,9,9)-diphosphate. Bis-(pr0poximethyl-anthracenetriyl) (1,1,8,8,9,9)-diphosphate. Bis-(propoxiethyl-anthracenetriyl)(1,1,8,8,9,9)-diphosphate. Bis-(isopropoximethyl-anthracenetriyl)(1,1,8,8 ,9,9)-diphosphate. Bis-(isopropoxiethyl-anthracenetriyl) (1,1,8,8,9,9)-diph0sphate.

Substituted anthrone reagent 3-(ethioxiethyl)-1,8-dihydroxy-Q-authrone.S-(ethioximethyl) -1,8-dihydroxy-Q-anthrone.3-(pr0poxipropyl)-1,8-dihydroxy-Q-anthrone. 3-(isopr0poxiisopropyl)-1,8- dihydroxy-Q-anthrone.3-(pr0poximethyl)-l,8-dihydroxy-Q-anthrone.3-(propoxiethyl)-1,8-dihydroxy-Q-anthrone. 3-(isopropoximethyl)-1,8di-

hydroxy-Q-anthrone. 3-(is0prop0xiethyl)1,8-dihydroxy-Q-anthrone.

Each of the aforesaid phosphorylated compounds exists in three otherforms with the following postulated structural formula:

ethioxiethyl, ethoximethyl, propoxipropyl, isopropoxi-isopropyl,propoximethyl, propoxiethyl, isopropoximethyl, and isopropoxiethyl and Wand Y are hydrogen atoms, and the 3,6 substituted compound, wherein Xand Y is an alkyloxialkyl group and W and Z are hydrogen atoms, and the6,6 substituted compound wherein W and Y are alkyloxialkyl groups and Xand Z are hydrogen atoms.

Each of the aforesaidbis-(a1kyloxialkyl-anthracenetriyl)-(l,1,8,8,9,9)-diphosphate compoundsis a yellow to brown crystalline compound without odor and melting above300 C. The respective new compounds are insoluble in water, slightlysoluble in alcohol and propylene glycol but often soluble in acetone andchloroform and have a characteristic infra-red spectra.

EXAMPLE 8 In place of the pyridine used in Examples 1 through 7 theremay be substituted in equal volumes, other liquid tertiary amine such asquinolines, picolines, N-methylpiperidine, N-methyl-morpholine,trimethylamine, triethylamine, tripropylamine and tri-isopropylamine.The remainder of the steps are the same and the respective compoundobtained is the same in every respect as that resulting from Examples 1through 7 above.

EXAMPLE 9 When an ointment containing the new compound is desired, thena therapeutically sufiicient quantity of the selected new compoundobtained as a result of Examples 1 to 8 above, is mixed with anappropriate quantity of an acceptable ointment vehicle. An optimalconcentration of active ingredient used to prepare such an ointment isfrom 0.1 percent to 20 percent by weight with a preferred range ofconcentration of active ingredient being from 2 percent to 10 percent byweight. Suitable ointments may be prepared with either an oleaginouscarrier as for example, petrolatum, a hydrophilic or lipophilic emulsionointment base and a water-soluble ointment base. Typical ointmentcompositions of the type set forth above may be prepared as follows:

(a) Oleaginous ointment:

Gm. Dianthracenetriyl (1,1',8,8'9,9')-diphosphate l0 Petrolatum U.S.P.q.s 100 Melt approximately 80 grams of the petrolatum using care not tooverheat. The dianthracenetriyl-(1,1,8,8',9,9')- diphosphate is thenadded and the whole stirred until a uniform dispersion is achieved. Themixture is then brought to desired weight with additional petrolatum andallowed to cool to room temperature while stirring. The ointment is thenpackaged in unit containers and is ready for dispersing.

(b) Water-in-oil emulsion base:

Dimethyl-dianthracenetriyl-(1,1',8,8,9,9,) diphosphate Cholesterol 3Stearyl alcohol 3 White wax 8 Petrolatum q.s 100 Melt the stearylalcohol, white wax and about 60 gms. of

the white petrolatum on a steam bath. Add the cholesterol and stir untilall have dissolved. In a separate container, melt about 3gms. ofpetrolatum and then add the dimethyl-dianthracenetriyl-(1,1',8,8,9,9')diphosphate and stir until a smooth paste results. Add this mixture tothe stearyl alcohol, white wax and petrolatum, mixing well. Bring toproper Weight with additional white petrolatum and stir until congealed.

The resultant ointment base may be used in the anhydrous oleaginous formor mixed with water to form a water-in-oil emulsion base. If it isdesired to prepare the (c) Oil-in-water emulsion base:

Di(methyloximethyl-dianthracecenetriyl (l,l,8,8',9,9')-diphosphate 2Cetyl alcohol 15 White wax 1.5 Propylene glycol 10 Sodium lauryl sulfate2 Water q.s.

Melt the cetyl alcohol and white wax with one-half the weight ofpropylene glycol, avoiding heating above 60 C. The remainder of thepropylene glycol is mixed with the di(methoximethyl) dianthracenetriyl(l,1,8,8', 9,9')-diphosphate and stirred until a smooth paste isobtained and this then added to the molten cetyl alcoholwhite waxmixture with stirring. The sodium lauryl sulfate is dissolved in about40 gms. of water with the aid of heat. The oil phase is slowly added tothe water phase with rapid stirring. After about five minutes of rapidstirring, the mixture is brought to appropriate weight with additionalwarm water and the whole stirred until congealed. The oil-in-wateremulsion base thus formed is then milled or homogenized and packagedinto suitable unit containers.

A vanishing cream may also be used as a carrier for the active compound,in which case a therapeutically sufiicient quantity of the desiredphosphorylated anthracenetriol compound, described above, is mixed withsulficient cold cream to form a pharmaceutically acceptable ointmentpreparation.

(d) Water-soluble ointment base: Gm. Di(chloromethyl)dianthracenetriyl-(1,l',8,8, 9,9')-diphosphate Polyethylene glycol-40040 Polyethylene glycol-4000 q.s. 100

Warm equal weights of the glycol components to form a uniform mixture.Add the selected phosphorylated anthracenetriol compound and stir untilcongealed.

The degree of hardness of the ointment may be varied by replacing aportion of the polyethylene glycol-400 with polyethylene glycol-4000.Between 5 :percent and 25 percent of water may be incorporated into thebase in which event, approximately 10 percent of the weight ofpolyethylene glycol-4000 utilized is replaced with an equal weight ofstearyl alcohol.

It may be found desirable to use other polyethylene glycol compounds inpreparing the ointment base as for example, polyethylene glycol with amolecular weight between 200 and 800 to replace a portion or the entirequantity of polyethylene glycol-400 and a polyethylene glycol compoundhaving a molecular weight of between 1,000 and 6,000 in place of aportion or the entire portion of the polyethylene glycol-4000.

In place of any of the above described phosphorylated anthracenetriolcompounds there may be substituted any other of the phosphorylatedanthracenetriol compounds described in Examples 1 to 7 above, theconcentration of said active ingredient to be between 0.1 percent and 20percent by weight depending upon the patients need.

EXAMPLE 10 When it is desired to utilize a lotion as the therapeuticdosage form then this may be prepared by suspending the appropriatequantity of the selected active ingredient in a pharmaceuticallyacceptable lotion vehicle. The range in 13 concentration of the activeingredient is from. 0.1 percent to 20 percent by weight with a preferreddosage range being from 3 percent to percent by weight.

A lotion containing dianthratriol-(1,1',8,8',9,9')-diphosphate isprepared by levigating 2.5 gm. of dianthratriol-(1,1',8,8',9,9')-diphosphate with ml. of ethyl alcohol and 20 gm. ofglycerin. In another vessel a solution of 0.1 percent (by weight) ofmethyl cellulose in water is prepared and an appropriate quantity of themethyl cellulose solution is added to the alcohol-glycerin triturate ofthe active ingredient so that the total final Weight is 100 gm. Thewhole is then homogenized to form a lotion suitable for therapeutic use.

As an alternate vehicle, an equivalent volume of a bland, vegetable oilas for example, sesame-seed oil, peanut oil or cotton-seed oil, may besubstituted for the alcohol described above. In this instance, from 0.1to 3.0 percent by weight of a surface-active agent, as for example,sodium lauryl sulfate is added to the methyl cellulose solution prior toits addition to the oil-glycerin triturate. After homogenizing, apharmaceutically acceptable emulsion lotion results. The viscosity ofthis lotion may be adjusted by the addition of either oil or water,depending on the nature of the external emulsion phase.

EXAMPLE 11 It may be desired to utilize the new phosphorylatedanthracenetriol compounds described in Examples 1 through 7 above in theform of a shampoo or a solid detergent cleansing bar. In theseinstances, the conventional alkaline preparations should be avoidedsince an alkaline reacting preparation would tend to decompose theactive substance to form a red lake. In preparing these cleansingcompositions a non-ionic detergent compound is preferred although incertain instances sodium lauryl sulfate may be used provided the pH ofthe resultant preparation is maintained below pH 6. The range ofconcentration of the active phosphorylated anthracenetriol compound inthe aforesaid liquid or solid cleansing preparation is from 0.1 percentto 20 percent by weight, with a preferred concentration of from 2 to 10percent by weight.

Detergent shampoos may be prepared as follows:

(a) Water base shampoos: Gm. Dianthratriol-(l,1',8,8',8,9)-diphosphate10 Glycerin 5 Sodium lauryl sulfate 5 Water q.s 100 The sodium laurylsulfate is dissolved in about 60 cc. of water. The phosphorylatedanthracenetriol compound is mixed with the glycerin to form a smoothpaste and this is suspended in the sodium lauryl sulfate solution. Wateris then added to proper volume. If it is desired to use a suspendingagent, then 2 percent of carboxymethyl cellulose may be added, makingappropriate adjustment in the water added to bring to final volume.

(b) Oil base shampoos: Gm. Di (chloromethyl) -dianthracenetriyl l l',8,8',

9,9')-di phosphate 20 Tween 80 2O Tween 20 4 Cotton-seed oil, q.s 100The Tween compounds are dissolved in about 40 grams of the oil and tothis is added the phosphorylated anthracenetriol compound. The mixtureis brought to final volume with additional cotton-seed oil.

Should it be desired to use an emulsion shampoo then from 5 to parts byweight of water may be mixed with the oil base shampoo and the wholehomogenized. In place of the cotton-seed oil used above there may besubstituted peanut oil, sesame oil, olive oil, or a bland vegetable oil.In place of the Tween compounds described above there may be substitutedany other nonionic detergent, as for example, Pluronic or sodium laurylsulfate.

. 14 Solid detergent bars containing the new phosphorylatedanthracenetriol compound may be prepared by incorporating a compoundobtained as a result of Examples 1 to 8 above, with a carriercomprising:

Parts Non-ionic detergent 35 Talc l0 Diluent 55 The solid ingredientsare mixed, milled and extruded into a bar. The bar is then shredded andmixed with a therapeutically sufficient quantity of the selectedphosphorylated anthracenetriol compound and then shaped into a cake ofsuitable size.

The proportion of ingredients described above may be varied to meetspecial needs. Thus the range in concentration of detergent may bebetween 15 percent and 35 percent, whereas the hardening agent, such astalc, may be between 5 percent and 15 percent, with the remainder beingdiluent. Appropriate diluents are polyoxyethylene glycols having amolecular weight of 1,000 to 6,000, cetyl alcohol, stearly alcohol,hydrogenated coconut oil, oil, stearic acid, and mixtures of these.Suitable detergents are any anionic detergent as for example, the polyoxyethylene sorbitan oleates, steal-ates and laurates, the pluronicseries of compounds or the neutronyx series of detergents or mixtures ofthese. Sodium lauryl sulfate and Igepon may be utilized. It may bepreferred to utilize a neutral soap as a carrier for the activecompounds in which case such soaps must have a pH not above pH 6 to beadvantageously used. Such soap compositions are first reduced to apowder, mixed with the active ingredient and then shaped into bars ofsuitable size.

The liquid and solid detergent compositions are applied directly to theaffected area which has been previously moistened with water. A richlather is developed and allowed to remain for a period of two to fiveminutes and then rinsed with water. The treatment may be repeated ifnecessary. While the cleansing of the affected skin may be conducted asoften as is required, the shampoo treatment of the hair and the scalp iscarried out from one to four times weekly although in certainconditions, it may be required once daily.

EXAMPLE 12 In certain circumstances it may be found desirable to utilizethe active ingredient directly on the lesion. In these circumstances thepure chemical substance, obtained as a result of Examples 1 through 8above, is micronized and the resultant micronized powder is placed incontact with the affected area at least once daily. Such treatment is anextreme form of therapy desired to produce an acute cellular tissueresponse and is not a customary procedure but may be desirably utilizedin therapy.

'EXAMPLE 13 When it is desired to utilize the compositions described inExamples 9 through 12 in therapy, then the appropriate selected agent isapplied to the affected area from one to six times daily, depending onthe nature and type of lesion being treated, as well as the severity ofthe disease and the condition of the patient.

When :psoriasis is being treated with a composition containing the newcompounds as described above, then preferred unit dosage forms areointments or lotons, although special patient needs may direct apreference for the other dosage forms as well as a combination of these.When the psoriatic lesion is dry and crusted, then the ointment or thelotion is preferred and often a combination of both will be used. For aweeping-open lesion, a hydrophilic preparation such as the lotion orhydrophilic ointment is preferred. Thus, it is seen that all of thedosage forms have a special use in the treatment of psoriasis.

When it is desired to treat a psoriatic lesion the selected dosage formis applied to the affected area from one to six times daily. The sitemay be bandaged (or not) depending on the patients and clinicianspreference. A resolution of the psoriatic disease will be observed aftera relatively short period of therapy as for example, from one to threeweeks, and the disease will be brought under continued control by theapplication of maintenance therapy with compositions containing theselected active ingredients described above.

Similar therapeutic beneficial effects will be observed after theapplication of the appropriate above-described compositions to aneczematoid lesion and seborrhea. When an eczematoid lesion and seborrheaare treated with compositions containing the new compounds described inExamples 1 through 8 then the preparation is applied from one to sixtimes daily. After three to four days of therapy, a beneficial responseis observed which is continued with maintenance therapy. Maintenancetherapy regimens may provide for a minimal frequency of application tothe affected area of from once weekly to a frequency of several timesdaily. The frequency of application of the compositions will dependentirely on the patients medical history, severity of disease and theresponse to therapy.

'EXAMPLE 14 In the treatment of eczema, psoriasis, seborrhea andscleraderma, it will be found desirable to incorporate from 0.1 percentto percent of an anti-inflammatory compound as for example, cortisone,hydrocortisone, hydrocortisone acetate, prednisolone or other steroidcompounds having tissue anti-inflammatory properties into compositionscontaining the phosphorylated anthracenetriol compound. Thus, any one ofthe aforesaid steroid agents may be mixed in a therapeuticallysufficient quantity into an ointment, lotion, shampoo or detergent cakecontaining the new phosphorylated anthracenetriol compound. The methodof use and the frequency of application remain the same but asynergistic action occurs in that a lesion previously refractory toother forms of therapy will now be found to respond and to be broughtinto therapeutic control.

What is claimed is:

1. A compound of the structure WU X O;P})\P%)0 wherein W, X, Y and Z areselected from the group consisting of hydrogen, methyl, chloromethyl,carboxy, carbomethoxy, carboethoxy, methylacetate, ethylacetate,methoxy, methoxymethyl, acetoxymethyl, acetox'yethyl,

chloro and nitro groups.

2. The compound of claim 1, said compound beingdianthracenetriyl-(1,1,8,8,9,9')-diphosphate.

3. The compound of claim 1, said compound being(3,3')(3,6)(6,6)-dimethyl dianthracenetriyl-(1,l,8,8, 9,9')-diphosphate.

4. A compound of claim 1, said compound beingdianthracenetriyl-(l,1',8,8',9,9')-diphosphate (3,3') (3,6') (6, 6-diethyl-acetate) 5. A compound of claim 1, said compound beingdicarboxy-dianthracenetriyl- 1,1',8,8,9,9')-diphosphate.

6. A compound of claim 1, said compound being diacetoxymethyldianthracenetri'yl-(l,l',8,8,9,9')-disphosphate.

7. A compound of claim 1, said compound being dichloromethyldianthracenetriyl (1,1,8,8',9,9')-disphos phate.

8. A compound of claim 1, said compound being dimethoxymethyldianthracenetriyl-(1,1,8,8',9,9)-diphosphate.

9. A compound of claim 1, said compound beingdichloro-dianthracenetriyl-( 1,1',8,8,9,9)-diphosphate.

10. A compound of claim 1, said compound beingdinitro-dianthracenetriyl-( 1,1, 8,8,9,9' -diphosphate.

11. The method for preparing a compound of claim 1 comprising the stepsof:

(a) adding an hydroxyanthracene compound selected from the groupsconsisting of anthralin, 11,8-dihydroxy 9 anthrone, 3-methyl 1,8dihydroxy-9- anthrone, 3-chloro-1,8-dihydroxy-9-anthrone, 3-carboxy 1,8dihydroxy 9 anthrone, 3-methoxy-1,8- dihydoxy-9-anthrone, 3-acetoxy 1,8dihydroxy-9- anthrone, 3 acetoxymethyl 1,8 dihydroxy-9-anthron, 3-chloro1,8 dihydroxy-9-anthrone, 3-nitrol,8-dihydroxy-9-anthrone,B-methyI-anthralin, 3-chloromethyl-anthralin, 3-carboxy-anthralin,3-methoxyanthralin, 3 acetoxy anthralin, 3-acetoxymethylanthralin,3-chloro-anthralin, 3-nitro-anthralin to 200 ml. of tertiaryaminesolvent; 1

(b) adding phosphorus oxychloride to aforesaid tertiary amines solution,

(c) warming, filtering, and,

(d) recovering the formed correspondingdianthracenetriyl-(1,1',8,8',9,9')-disphosphate compound therefrom.

12. The method of claim 11 said hydroxyanthracene compound beingl1,8-dihydroxyanthraquinone and recoverin g dianthracenetriyl-1,1',8,8,9,9')-diphosphate therefrom.

13. The method of claim 11 said hydroxyanthracene compound beinganthralin and recovering dianthracenetriyl-( 1,1 ,8,8',9,9'-'disphosphate therefrom.

14. The method of claim 11, said hydroxyanthracene compound being3-methyl-1,8,9, trihydrox'yanthracene and recovering dimethyldianthracenetriyl-(1,1',8,8,9,9')-diphosphate therefrom.

References Cited UNITED STATES PATENTS 3,008,951 11/1961 Ferno et al260-974 XR ANTON H. SUTTO, Primary Examiner US. Cl. X.R.

